CST–polymerase α-primase solves a second telomere end-replication problem

Hiroyuki Takai, Valentina Aria, Pamela Borges, Joseph T. P. Yeeles () and Titia Lange ()
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Hiroyuki Takai: Rockefeller University
Valentina Aria: Medical Research Council Laboratory of Molecular Biology
Pamela Borges: Rockefeller University
Joseph T. P. Yeeles: Medical Research Council Laboratory of Molecular Biology
Titia Lange: Rockefeller University

Nature, 2024, vol. 627, issue 8004, 664-670

Abstract: Abstract Telomerase adds G-rich telomeric repeats to the 3′ ends of telomeres1, counteracting telomere shortening caused by loss of telomeric 3′ overhangs during leading-strand DNA synthesis (‘the end-replication problem’2). Here we report a second end-replication problem that originates from the incomplete duplication of the C-rich telomeric repeat strand (C-strand) by lagging-strand DNA synthesis. This problem is resolved by fill-in synthesis mediated by polymerase α-primase bound to Ctc1–Stn1–Ten1 (CST–Polα-primase). In vitro, priming for lagging-strand DNA replication does not occur on the 3′ overhang and lagging-strand synthesis stops in a zone of approximately 150 nucleotides (nt) more than 26 nt from the end of the template. Consistent with the in vitro data, lagging-end telomeres of cells lacking CST–Polα-primase lost 50–60 nt of telomeric CCCTAA repeats per population doubling. The C-strands of leading-end telomeres shortened by around 100 nt per population doubling, reflecting the generation of 3′ overhangs through resection. The measured overall C-strand shortening in the absence of CST–Polα-primase fill-in is consistent with the combined effects of incomplete lagging-strand synthesis and 5′ resection at the leading ends. We conclude that canonical DNA replication creates two telomere end-replication problems that require telomerase to maintain the G-rich strand and CST–Polα-primase to maintain the C-strand.

Date: 2024
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DOI: 10.1038/s41586-024-07137-1

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